EP2308292A2 - Appareil pour tenir d'organes - Google Patents

Appareil pour tenir d'organes Download PDF

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Publication number
EP2308292A2
EP2308292A2 EP10182445A EP10182445A EP2308292A2 EP 2308292 A2 EP2308292 A2 EP 2308292A2 EP 10182445 A EP10182445 A EP 10182445A EP 10182445 A EP10182445 A EP 10182445A EP 2308292 A2 EP2308292 A2 EP 2308292A2
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EP
European Patent Office
Prior art keywords
organ
perfusion
transporter
medical fluid
pressure
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP10182445A
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German (de)
English (en)
Other versions
EP2308292A3 (fr
EP2308292B1 (fr
Inventor
Donald R. Owen
David C. Kravitz
John Brassil
Kelvin G. M. Brockbank
Andrews Burroughs
Dennis J. Steibel
Dickon Isaacs
Richard Fraser
Stanley Harris
Douglas Schein
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Organ Recovery Systems Inc
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Organ Recovery Systems Inc
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Publication date
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Publication of EP2308292A2 publication Critical patent/EP2308292A2/fr
Publication of EP2308292A3 publication Critical patent/EP2308292A3/fr
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Publication of EP2308292B1 publication Critical patent/EP2308292B1/fr
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    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N1/00—Preservation of bodies of humans or animals, or parts thereof
    • A01N1/02—Preservation of living parts
    • A01N1/0236—Mechanical aspects
    • A01N1/0263—Non-refrigerated containers specially adapted for transporting or storing living parts whilst preserving, e.g. cool boxes, blood bags or "straws" for cryopreservation
    • A01N1/0273—Transport containers
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N1/00—Preservation of bodies of humans or animals, or parts thereof
    • A01N1/02—Preservation of living parts
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N1/00—Preservation of bodies of humans or animals, or parts thereof
    • A01N1/02—Preservation of living parts
    • A01N1/0236—Mechanical aspects
    • A01N1/0242—Apparatuses, i.e. devices used in the process of preservation of living parts, such as pumps, refrigeration devices or any other devices featuring moving parts and/or temperature controlling components
    • A01N1/0247—Apparatuses, i.e. devices used in the process of preservation of living parts, such as pumps, refrigeration devices or any other devices featuring moving parts and/or temperature controlling components for perfusion, i.e. for circulating fluid through organs, blood vessels or other living parts

Definitions

  • the invention relates to an apparatus and method for perfusing one or more organs to monitor, sustain and/or restore the viability of the organ(s) and/or for transporting and/or storing the organ(s).
  • a-GST alpha glutathione-S-transferase
  • p-GST Pi glutathione-S-transferase
  • Wikman-Coffelt teaches perfusing or washing an organ at a warm temperature with a first preservation solution containing pyruvate for removal of blood or other debris from the organ's vessels and to vasodilate, increase flow and load the cells with an energy supply in the form of a clean substrate, namely the pyruvate. Wikman-Coffelt teaches that the pyruvate prevents edema, ischemia, calcium overload and acidosis as well as helps preserve the action potential across the cell membrane.
  • the organ is then perfused with a second perfusion solution containing pyruvate and a small percentage of ethanol in order to stop the organ from working, vasodilate the blood vessels allowing for full vascular flow, continue to load the cells with pyruvate and preserve the energy state of the organ. Finally the organ is stored in a large volume of the first solution for 24 hours or longer at temperatures between 4°C and 10°C.
  • the mitochondria are the source of energy in cells and need significant amounts of oxygen to function. Organs naturally have significant pyruvate levels, and providing an organ with additional pyruvate will not assist in restoring and/or maintaining an organ's full physiological function if the mitochondria are not provided with sufficient oxygen to function. Further, briefly flooding an organ with pyruvate may, in fact, facilitate tearing off of the vascular endothelial lining of the organ.
  • the present invention focuses on avoiding damage to an organ during perfusion while monitoring, sustaining and/or restoring the viability of the organ and preserving the organ for storage and/or transport.
  • the invention is directed to an apparatus and method for perfusing an organ to monitor, sustain and/or restore the viability of the organ and/or for transporting and/or storing the organ. More particularly, the organ perfusion apparatus and method according to the invention monitor, sustain and/or restore organ viability by perfusing the organ at hypothermic temperature (hypothermic perfusion mode) and/or normothermic temperatures (normothermic perfusion mode) preferably after flushing of the organ such as by hypothermic flushing followed by static organ storage and/or organ perfusion at hypothermic temperatures for transport and/or storage of the organ.
  • hypothermic temperature hypothermic temperature
  • normothermic temperatures normothermic temperatures
  • the medical fluid preferably contains little or no oxygen and preferably includes antioxidants, both molecular (e.g., 2-ascorbic acid tocopherol) and enzymatic (e.g., catalase and superoxide dismutase (SOD)).
  • antioxidants both molecular (e.g., 2-ascorbic acid tocopherol) and enzymatic (e.g., catalase and superoxide dismutase (SOD)).
  • SOD superoxide dismutase
  • normothermic and/or hypothermic perfusion, and preferably hypothermic perfusion can be performed in vivo as well as in vitro. Such perfusion arrests ischemic injury in preparation for transport, storage and/or transplant of the organ.
  • the normothermic treatment is preferably employed after an organ has been subjected to hypothermic temperatures, statically and/or under perfusion. Such initial hypothermic exposure can occur, for example, during transport and/or storage of an organ after harvesting.
  • the treatment is also suitable for organs that will ultimately be stored and/or transported under hypothermic conditions. In other words, the treatment can be applied to organs prior to cold storage and/or transport.
  • gravity can be used to feed the medical fluid into the organ from the intermediary tank, if appropriate.
  • the organ may be perfused directly from a pump, such as a roller pump or a peristaltic pump, with proper pump control and/or sufficiently fail-safe controllers to prevent overpressurization of the organ, especially as a result of a system malfunction. Substantially eliminating overpressurization prevents or reduces damage to the vascular endothelial lining of the organ and to the organ tissue in general, in particular at hypothermic temperatures when the organ has less ability to protect itself by vascular constriction.
  • the perfusion apparatus may be used for various organs, such as the kidneys, and may be adapted to more complex organs, such as the liver, having multiple vasculature structures, for example, the hepatic and portal vasculatures of the liver.
  • the present invention also provides an organ transporter which allows for transportation of an organ over long distances.
  • the organ transporter may be used for various organs, such as the kidneys, and may be adapted to more complex organs, such as the liver, having multiple vasculature structures, for example, the hepatic and portal vasculatures of the liver.
  • the organ transporter includes features of an organ perfusion apparatus, such as sensors and temperature controllers, as well as cassette interface features.
  • Figure 1 shows an organ perfusion apparatus 1 according to the invention.
  • Figure 2 is a schematic illustration of the apparatus of Fig. 1 .
  • the apparatus 1 is preferably at least partially microprocessor controlled, and pneumatically actuated.
  • the microprocessor 150 connection to the sensors, valves, thermoelectric units and pumps of the apparatus 1 is schematically shown in Fig. 3 .
  • Microprocessor 150 and apparatus 1 may be configured to and are preferably capable of further being connected to a computer network to provide data sharing, for example across a local area network or across the Internet.
  • the organ perfusion apparatus 1 is capable of perfusing one or more organs simultaneously, at both normothermic and hypothermic temperatures (hereinafter, normothermic and hypothermic perfusion modes). All medical fluid contact surfaces are preferably formed of or coated with materials compatible with the medical fluid used, more preferably non-thrombogenic materials. As shown in Fig. 1 , the apparatus 1 includes a housing 2 which includes front cover 4, which is preferably translucent, and a reservoir access door 3. The apparatus preferably has one or more control and display areas 5a, 5b, 5c, 5d for monitoring and controlling perfusion.
  • an on board compressor unit as any adequate pressure source can be employed, for example, a compressed gas (e.g., air, CO 2 , oxygen, nitrogen, etc.) tank (not shown) preferably with a tank volume of 1.5 liters at 100 psi or greater for internal pressurization.
  • a compressed gas e.g., air, CO 2 , oxygen, nitrogen, etc.
  • an internally pressurized reservoir tank (not shown) may be used.
  • Reservoir tanks 15a, 15b, 17 may, in embodiments, be bottles or other suitably rigid reservoirs that can supply perfusate by gravity or can be pressurized by compressed gas.
  • Gas valves 22-23 are provided on the gas tube 26 to allow for control of the pressure provided by the onboard compressor unit 21.
  • Anti-back flow valves 24a, 24b may be provided respectively on the gas tubes 26a, 26b.
  • Pressure sensors P5, P6 may be provided respectively on the gas tubes 26a, 26b to relay conditions therein to the microprocessor 150, shown in Fig. 3 .
  • Perfusion, diagnostic and/or transporter apparatus may be provided with sensors to monitor perfusion fluid pressure and flow in the particular apparatus to detect faults in the particular apparatus, such as pressure elevated above a suitable level for maintenance of the organ.
  • Gas valves GV 1 and GV 2 may be provided to release pressure from the cuffs 16a, 16b.
  • the medical fluid is preferably synthetic and may, for example, be a simple crystalloid solution, or may be augmented with an appropriate oxygen carrier.
  • the oxygen carrier may, for example, be washed, stabilized red blood cells, cross-linked hemoglobin, pegolated hemoglobin or fluorocarbon based emulsions.
  • the medical fluid may also contain antioxidants known to reduce peroxidation or free radical damage in the physiological environment and specific agents known to aid in tissue protection.
  • an oxygenated (e.g., cross-linked hemoglobin-based bicarbonate) solution is preferred for the normothermic mode while a non-oxygenated (e.g., simple crystalloid solution preferably augmented with antioxidants) solution is preferred for the hypothermic mode.
  • the perfusion solution may be provided in a perfusion solution kit, for example, a saleable package preferably containing at least one first container holding a first perfusion solution for normothermic perfusion and at least one second container holding a second, different perfusion solution for hypothermic perfusion, optionally the box 10 shown in Fig. 2 .
  • the first perfusion solution may contain at least one oxygen carrier, may be oxygenated and/or may be selected from the group consisting of a cross-linked hemoglobin and stabilized red blood cells.
  • the second perfusion solution may be non-oxygenated, may contain at least one anti-oxidant, and/or may contain at least one vasodilator. Additionally, the solution preferably contains no more than 5 mM of dissolved pyruvate salt.
  • the perfusion solution kit may contain at least one first container holding a first perfusion solution for hypothermic perfusion at a first temperature and at least one second container holding a second, different perfusion solution for hypothermic perfusion at a second temperature lower than the first temperature.
  • the first perfusion solution may contain at least a crystalloid and may contain at least one vasodilator.
  • the second perfusion solution may be oxygen carrier enhanced, where the oxygen carrier is selected from the group consisting of a hemoglobin and stabilized red blood cells.
  • the second perfusion solution may, if desired, contain at least one anti-oxidant or free radical scavenger.
  • the second solution contains no more than 5 mM of dissolved pyruvate salt.
  • the first container and the second container may be configured to be operably connected to a perfusion machine as perfusion fluid reservoirs in fluid communication with perfusate conduits of said perfusion machine.
  • one of the first and second containers may be compressible to apply pressure to the perfusion solution therein.
  • at least one of the first and second containers may include a first opening for passage of a contained perfusion solution out of the container and a second opening passage of a compressed gas into the container.
  • the package may be a cassette configured to be operably connected to a perfusion machine for connection of the first and second containers within the cassette in fluid communication with perfusate conduits or tubing of the perfusion machine.
  • An organ chamber 40 which supports a cassette 65, as shown in Fig. 2 , which holds an organ to be perfused, or a plurality of cassettes 65,65,65, as shown in Fig. 12 , preferably disposed one adjacent the other.
  • Various embodiments of the cassette 65 are shown in Figs. 11A-11D .
  • the cassette 65 is preferably formed of a material that is light but durable so that the cassette 65 is highly portable. The material may also be transparent to allow visual inspection of the organ.
  • Each cassette 65 may also be provided with its own stepping motor/cam valve 75 (for example, in the handle portion 68, as shown in Fig. 11 C) for fine tuning the pressure of medical fluid perfused into the organ 60 disposed therein, discussed in more detail below.
  • pressure may, in embodiments, be controlled by way of a pneumatic chamber, such as an individual pneumatic chamber for each organ (not shown), or by any suitable variable valve such as a rotary screw valve or a helical screw valve.
  • Cassette 65 and/or both lids 410 and 420 may be constructed of an optically clear material to allow for viewing of the interior of cassette 65 and monitoring of the organ and to allow for video images or photographs to be taken of the organ.
  • Perfusion apparatus 1 or cassette 65 may be wired and fitted with a video camera or a photographic camera, digital or otherwise, to record the progress and status of the organ. The captured images may be made available over a computer network such as a local area network or the Internet to provide for additional data analysis and remote monitoring.
  • Organ chair 1800 may also be raised and lowered within cassette 65 to facilitate sampling from venous outflow sampler 1810. Alternatively, a sufficient amount of the organ bath may be drained from cassette 65 to obtain access to venous outflow sampler 1810 or to capture venous outflow before the outflow mixes with the rest of the perfusate in the organ bath.
  • Organ chair 1800 is preferably additionally configured with a cannula 1820 that attaches to the perfused artery, such as the renal artery.
  • Cannula 1820 may be reusable or may be suitable for single-use, preferably provided in a sterile package with cassette 65, organ chair 1800 and tubeset 400.
  • Cannula 1820 is provided with a cannula clamp 1830 to secure cannula 1820 around the perfused artery and to preferably provide leak-tight perfusion.
  • a straight-in flanged cannula may also be used, however clamping around the artery is preferable to prevent contact with the inner surface of the artery, which is easily damaged.
  • Cannula 1820 may also be configured with additional branching connections for accessory arteries.
  • Cannula clamp 1830 may be a clam-shell configuration or may be a two-part design. Cannula clamp 1830 may be configured with integral or separate means for tightening cannula clamp 1830 to the proper pressure to provide leak-tight perfusion.
  • cannula 1820 may be provided with a snap 1840 to hold cannula 1820 closed.
  • Cannula 1820 may also be provided with a vent 1850 to remove air bubbles from cannula 1820.
  • Organ chair 1800, cannula 1820 and/or cannula clamp 1830 may be constructed of an optically clear material to facilitate monitoring of the organ and perfusion status.
  • the organ when transported, the organ is disposed on the organ supporting surface 66 and the cassette 65 is preferably enclosed in a preferably sterile bag 69, as shown, for example, in Fig. 11A .
  • a sterile bag 69 When the organ is perfused with medical fluid, effluent medical fluid collects in the bag 69 to form an organ bath.
  • the cassette 65 can be formed with a fluid tight lower portion in which the effluent medical fluid may collect, or the effluent medical fluid may collect in the organ chamber 40 to form the organ bath.
  • the bag 69 would preferably be removed prior to inserting the cassette into the organ chamber 40.
  • an organ chamber may be provided for each organ.
  • cassette 65 can be transported in the dual-lid cassette of Fig. 17 and additionally carried within a portable organ transporter.
  • Fig. 20 shows a cross-section view of a transporter 1900.
  • Transporter 1900 contains cassette 65 and pump 2010. Cassette 65 may be placed into and taken out of transporter 1900 without disconnecting tubeset 400 from cassette 65, thus maintaining sterility of the organ.
  • Sensors in transporter 1900 can detect the presence of cassette 65 in transporter 1900, and depending on the sensor, can read the organ identity from a barcode or radio frequency or other smart tag that may be integral to cassette 65. This allows for automated identification and tracking of the organ and helps monitor and control the chain of custody.
  • a global positioning system may be added to transporter 1900 and/or cassette 65 to facilitate tracking of the organ.
  • Transporter 1900 can be interfaced to a computer network by hardwire connection to a local area network or by wireless communication while in transit. This interface allows perfusion parameters, vascular resistance, and organ identification and transporter and cassette location to be tracked and displayed in real-time or captured for future analysis.
  • Transporter 1900 also preferably contains a filter 2020 to remove sediment and other particulate matter, preferably ranging in size from 0.05 to 15 microns in diameter or larger, from the perfusate to prevent clogging of the apparatus or the organ.
  • Transporter 1900 also contains batteries 2030, which may be located at the bottom of transporter 1900 or beneath pump 2010 or at any other location that provides easy access to change batteries 2030. Batteries 2030 may be rechargeable outside of transporter 1900 or while intact within transporter 1900 and/or are preferably hot-swappable one at a time. Batteries 2030 are preferably rechargeable rapidly and without full discharge.
  • Transporter 1900 may also provide an additional storage space 2040 at the bottom of transporter 1900 for power cords, batteries and other accessories.
  • Transporter 1900 may also include a power port for a DC hookup to a vehicle such as an automobile or airplane and/or for an AC hookup.
  • Bubble trap 2130 may be disposable and may be constructed integral to tubeset 400. Perfusate exiting bubble trap 2130 can either continue through infuse valve 2140 or wash valve 2150. Wash valve 2150 is normally open and infuse valve 2140 is normally closed. Preferably, wash valve 2150 and infuse valve 2140 operate dependently in an on/off manner, such that if one valve is open, the other valve is closed. Although infuse valve 2140 is normally closed, if the sensor and monitors all report suitable perfusion parameters present in transporter 1900, then infuse valve 2140 may be opened to allow organ perfusion.
  • infuse valve 2140 switches back to closed and wash valve 2150 is opened to divert fluid flow into the perfusate bath surrounding the organ.
  • This provides a failsafe mechanism that automatically shunts perfusate flow and prevents organ perfusion in case of a power failure or computer or electronics malfunction.
  • a pressure transducer 2120 such as designated by P 2 , may be hardwired, redundant to the computer and software control, to wash valve 2150 and infuse valve 2140 to quickly deliver a default message to the valves in the case of a pressure malfunction.
  • the diverted fluid may be separately collected in another container or compartment.
  • Fig. 22 shows various operation states of transporter 1900.
  • a user may select operations such as perfuse, idle, wash and prime.
  • Fig. 22 shows various options depending on the present state of transporter 1900.
  • the labels idle, prime, wash, perfuse and error handling indicate the state of transporter 1900 that is preferably displayed on control panel 1920 during the corresponding operation.
  • control panel 1920 displays the wash operation indicator, such as an LED display.
  • the arrows connecting the various operations of transporter 1900 indicate the manual and automatic actions that may occur to transition transporter 1900 between operation states. Manual actions require the user to act, for example by pressing a button or turning a knob or dial.
  • Automatic operations may be controlled by the passage of time and/or by an internal monitor within transporter 1900. Such automatic operation is shown in Fig. 22 , for example, connecting the prime operation to the idle operation. If the prime operation has been completed according to the internal transporter program parameters before the wash button has been pressed, transporter 1900 returns to an idle operation. Another automatic operation occurs during a perfuse operation if a fault or error occurs, such as overpressurization of the organ. When an error or fault occurs, transporter 1900 can move to an error handling operation to determine the extent or degree of the fault or error. If the fault or error is determined to be a small or correctable error, transporter 1900 moves into a wash operation.
  • Transporter 1900 may have an outer enclosure 2310 constructed of metal, or preferably a plastic or synthetic resin that is sufficiently strong to withstand penetration and impact.
  • Transporter 1900 contains insulation 2320, preferably a thermal insulation made of, for example, glass wool or expanded polystyrene. Insulation 2320 may be various thicknesses ranging from 0.5 inches to 5 inches thick or more, preferably 1 to 3 inches, such as approximately 2 inches thick.
  • Transporter 1900 is cooled by coolant 2110, which may be, e.g., an ice and water bath or a cryogenic material. In embodiments using cryogenic materials, the design should be such that organ freezing is prevented.
  • An ice and water mixture is preferably in an initial mixture of approximately 1 to 1, however, in embodiments the ice and water bath may be frozen solid.
  • Transporter 1900 can be configured to hold various amounts of coolant, preferably up to 10 to 12 liters.
  • An ice and water bath is preferable because it is inexpensive and can not get cold enough to freeze the organ.
  • Coolant 2110 preferably lasts for a minimum of 6 to 12 hours and more preferably lasts for a minimum of 30 to 50 hours without changing coolant 2110.
  • the level of coolant 2110 may be viewed through a transparent region of transporter 1900 or may be automatically detected and monitored by a sensor. Coolant 2110 can be replaced without stopping perfusion or removing cassette 65 from transporter 1900.
  • Coolant 2110 is maintained in a watertight compartment 2115 of transporter 1900. Compartment 2115 prevents the loss of coolant 2110 in the event transporter 1900 is tipped or inverted. Heat is conducted from the walls of the perfusion reservoir and cassette 65 into coolant 2110 enabling control within the desired temperature range. Coolant 2110 is a failsafe cooling mechanism because transporter 1900 automatically reverts to cold storage in the case of power loss or electrical or computer malfunction. Transporter 1900 may also be configured with a heater to raise the temperature of the perfusate.
  • Transporter 1900 and cassette 65 may accommodate various amounts of perfusate 2340, for example up to 3 to 5 liters. Preferably, approximately 1 liter of a hypothermic perfusate 2340 is used to perfuse organ 2350.
  • Organ 2350 may be various organs, including but not limited to a kidney, heart, lung, liver or small intestine.
  • Cassette 65 and transporter 1900 are preferably constructed to fit or mate such that efficient heat transfer is enabled.
  • the geometric elements of cassette 65 and transporter 1900 are preferably constructed such that when cassette 65 is placed within transporter 1900, the elements are secure for transport.
  • Fig. 24 shows various data structures and information connections that can be facilitated to assist in the overall communication and data transfers that may be beneficial before, during and after organ transplantation.
  • the perfusion apparatus, transporter, cassette, and organ diagnostic apparatus may be networked to permit remote management, tracking and monitoring of the location and therapeutic and diagnostic parameters of the organ or organs being stored or transported.
  • the information systems may be used to compile historical data of organ transport and storage, and provide cross-referencing with hospital and UNOS data on the donor and recipient.
  • the systems may also provide outcome data to allow for ready research of perfusion parameters and transplant outcomes. For example, information regarding the donor may be entered at the location where an organ is recovered from a donor. Information may also be directly recovered from the perfusion, diagnostic or transporter apparatus to monitor organ status and location.
  • the organ bath is preferably cooled to a predetermined temperature by a second thermoelectric unit 30b, as shown in Fig. 2 , in heat transfer communication with the organ chamber 40.
  • the medical fluid within reservoir 10 can be cooled utilizing a heat transfer device such as an ice and water bath or a cryogenic fluid heat exchanger apparatus such as that disclosed in co-pending Application No. 09/039,443, which is hereby incorporated by reference.
  • a temperature sensor T2 within the organ chamber 40 relays the temperature of the organ 60 to the microprocessor 150, which adjusts the thermoelectric unit 30b to maintain a desired organ temperature and/or displays the temperature on the control and display areas 5c for manual adjustment.
  • Medical fluid may be fed from the bag 15a directly to an organ 60 disposed in the organ chamber 40 through tubing 50a,50b,50c or from bag 15b through tubing 50d,50e,50c by opening valve LV 4 or LV 3, respectively.
  • Conventional medical fluid bag and tubing connections may be utilized. All tubing is preferably disposable, easily replaceable and interchangeable. Further, all tubing is preferably formed of or coated with materials compatible with the medical fluids used, more preferably non-thrombogenic materials. An end of the tubing 50c is inserted into the organ 60.
  • the tubing may beconnected to the organ(s) with conventional methods, for example, with sutures.
  • the tubing may include a lip to facilitate connection to the organ.
  • cannula 1820 described above may be used with or without connection to an organ chair 1800. However, the specific methods and connection depend on the type of organs(s) to be perfused.
  • the microprocessor 150 preferably controls the pressure source 20 in response to signals from the pressure sensor P1 to control the pressure of the medical fluid fed into the organ 60.
  • the microprocessor 150 may display the pressure on the control and display areas 5a, optionally for manual adjustment.
  • a fluid flow monitor F1 may also be provided on the tubing 50c to monitor the flow of medical fluid entering the organ 60 to indicate, for example, whether there are any leaks present in the organ.
  • the medical fluid may be fed from the reservoir tank 17 via tubing 51 into an intermediary tank 70 preferably having a pressure head of approximately 5 to 40 mm Hg. Medical fluid is then fed by gravity or, preferably, pressure, from the intermediary tank 70 to the organ 60 along tubing 50c by activating a valve LV 6 .
  • a level sensor 71 may be provided in the intermediary tank 70 in order to maintain the pressure head.
  • a bubble detection system may be installed to sense bubbles in the perfusate.
  • An air sensor and sensor board are preferably used.
  • the output of the sensor activates a debubbler system, such as an open solenoid valve, to rid bubbles from the perfusate flow prior to organ introduction.
  • the bubble detector may be positioned at any point in the system that is effective based on the particular parameters or design characteristics of the system.
  • a bubble detector and debubbler system BD may be positioned between the cam valve 205 and pressure sensor P1, as shown in Fig. 1 .
  • a stepping motor/cam valve 205 may be arranged on the tubing 50c to provide pulsatile delivery of the medical fluid to the organ 60, to decrease the pressure of the medical fluid fed into the organ 60, and/or to stop flow of medical fluid into the organ 60 if the perfusion pressure exceeds a predetermined amount.
  • a flow diverter or shunt line may be provided in the perfusion apparatus to which the fluid flow is diverted in the occurrence of a fault, such as excess pressure, for example by opening and closing a valve or a series of valves.
  • Specific embodiments of the stepping motor/cam valve are shown in Figs. 13A-13B and 14A-14F .
  • Figs. 13A-13B show a stepping motor/rotational type cam valve.
  • Fig. 13A is a top view of the apparatus.
  • Tubing for example, tubing 50c
  • Cam 200 is interposed between a support 203 and cam 200.
  • Cam 200 is connected by a rod 201 to stepping motor 202.
  • Fig. 13B is a side view of the apparatus. The dashed line shows the rotational span of the cam 200.
  • the cam 200 is in its non-occluding position. Rotated 180 degrees, the cam 200 totally occludes the tubing 50c with varying degrees of occlusion therebetween.
  • This stepping motor/cam valve is relatively fast, for example, with respect to the embodiment shown in Figs. 14A - 14F ; however, it requires a strong stepping motor.
  • Figs. 14A - 14F disclose another stepping motor/cam valve 210 according to the invention.
  • Fig. 14A is a side view of the apparatus while Fig. 14C is a top view.
  • Tubing for example, tubing 50c, is interposed between cam 220 and support 223.
  • the cam 220 is connected to stepping motor 222 by supports 221a - 221d and helical screw 225, which is connected to the stepping motor 222 via plate 222a.
  • Fig. 14B shows the supports 22 1 a and plate 222a in front view.
  • Fig. 14D where the support 221d is to the left of the center of the helical screw 225, the tubing 50c is not occluded.
  • Medical fluid expelled from the organ 60 which has collected in the bottom of the bag 69 (the cassette 65 or the organ chamber 40) is either pumped out through tubing 81 by a pump 80 for filtration, passing through a filter unit 82 and being returned to the organ bath, or is pumped out by a pump 90 for circulation through tubing 91.
  • the pumps 80, 90 are preferably conventional roller pumps or peristaltic pumps; however, other types of pumps may also be appropriate.
  • Fig. 25 shows a simplified schematic of a pump and pulse controller 2500 and the interaction of the pump and pulse controller with a perfusion apparatus, such as shown in Fig. 1 .
  • Pump and pulse controller 2500 receives pressure sensor data input 2510 from pressure sensor P and tachometer data input 2520.
  • a tachometer may be used to set the phase angle of the active wave.
  • Pump and pulse controller 2500 converts this information to motor drive output 2530, which powers pump 2540.
  • Fig. 25A shows various modes of operation that pump and pulse controller 2500 can provide and how pump and pulse controller 2500 eliminates pressure pulse waves from the perfusate flow and how it modulates perfusate flow rate while maintaining a constant pressure pulse rate.
  • FIG. 25A shows in the first mode of operation the waveforms that result from a constant drive speed applied to a peristaltic pump.
  • the second mode of operation shows how the pressure pulse wave can be eliminated or canceled out by applying a motor drive wave that is opposite to the pressure wave of the pump.
  • the third mode of operation called active waveform amplitude modulating, the pump pressure pulse wave is canceled by the motor drive wave, and a selected wave is added with a new amplitude as compared to the original pressure pulse wave amplitude.
  • the pump pressure pulse wave is canceled by the motor drive wave, and a selected wave is added with a new pulse width as compared to the original pressure pulse wave width.
  • the frequency may be modulated by adding a new frequency wave to the canceled waves.
  • a level sensor L2 in communication with the microprocessor 150 ensures that a predetermined level of effluent medical fluid is maintained within the organ chamber 40.
  • a temperature sensor T1 disposed in the tubing 91 relays the temperature of the medical fluid pumped out of the organ bath along tubing 91 to the microprocessor 150, which monitors the same.
  • a pressure sensor P2 disposed along the tubing 91 relays the pressure therein to the microprocessor 150, which shuts down the system if the fluid pressure in the tubing 91 exceeds a predetermined limit, or activates an alarm to notify the operator that the system should be shut down, for example, to clean filters or the like.
  • the mechanical relief valve prevents the pressure differential from attaining this level.
  • Immobilized pegolated carbonic anhydrase may be included in the hydrophilic coating. This allows bicarbonate to be converted to CO 2 and subsequently removed by vacuum venting. However, with organs such as kidneys which have the ability to eliminate bicarbonate, this may be unnecessary except in certain cases.
  • One of two gases preferably 100% oxygen and 95/5% oxygen/carbon dioxide, is placed on the opposite side of the membrane depending on the pH level of the diverted medical fluid.
  • another pump (not shown) may be provided which pumps effluent medical fluid out of the organ chamber 40 and through a viability sensor before returning it to the bath, or the viability sensor can be placed on tubing 81 utilizing pump 80.
  • the fluid characteristics may be analyzed in a separate diagnostic apparatus and/or analyzer as shown in Figs. 28-31 .
  • the sensed fluid characteristics such as organ resistance (pressure/flow), pH, pO 2 , pCO 2 , LDH, T/GST, Tprotein, lactate, glucose, base excess and ionized calcium levels may be used to analyze and determine an organ's viability.
  • the characteristics may be analyzed individually or multiple characteristics may be analyzed to determine the effect of various factors.
  • the characteristics may be measured by capturing the venous outflow of the organ and comparing its chemistry to the perfusate inflow.
  • the venous outflow may be captured directly and measured or the organ bath may be measured to provide a rough approximation of the fluid characteristics for comparisons over a period of time.
  • the organ viability index provides measurements and normal ranges for each characteristic, such as vascular resistance and perfusate chemistry characteristics based on pH, pO 2 , pCO 2 , LDH, T/GST, Tprotein, lactate, glucose, base excess and ionized calcium levels.
  • normal pH may be from 7.00 and 8.00, preferably from 7.25 and 7.75 and more preferably from 7.50 and 7.60 and base excess may be in the range of from -10 to -40, preferably from -15 to -30, and more preferably from -20 to -25.
  • Measurements that are outside the normal range may be indicated visually, e.g., by an asterisk or other suitable notation, aurally or by machine perceivable signals.
  • the characteristics give the physician insight into the metabolism of the organ, such as stability of the metabolism, consumption of glucose, creation of lactic acid and oxygen consumption.
  • the index may also provide identifying information, such as age, gender, blood type of the donor and any expanded criteria; organ information, such as organ collection date and time, warm ischemia time, cold ischemia time and vascular resistance; apparatus information, such as flow rate, elapsed time the pump has been operating and pressure; and other identifiers such as UNOS number and physician(s) in charge.
  • the index may additionally provide temperature corrections if desired.
  • the apparatus 5001 is formed of stackable modules.
  • the apparatus 5001 is capable of pumping a fluid through a system as well as oxygenating, filtering and/or debubbling the fluid.
  • the modules are each formed of a plurality of stackable support members and are easily combinable to form a compact apparatus containing desired components. Filtration, oxygenation and/or degassing membranes are disposed between the support members.
  • Figures 4-8 show various modules that may be stacked to form a combined pump, filtration, oxygenation and/or debubbler apparatus, such as the combined pump, filtration, oxygenation and debubbler apparatus 5001 shown in Figs. 9-10 .
  • the combined pump, filtration, oxygenation and debubbler apparatus 5001 is preferably formed of a plurality of stackable support members groupable to form one or more modules.
  • filtration, oxygenation and/or degassing membranes Interposed between the plurality of stackable support member are filtration, oxygenation and/or degassing membranes depending on a particular user's needs.
  • the filtration, oxygenation and/or degassing membranes are preferably commercially available macro-reticular hydrophobic polymer membranes hydrophilically grafted in a commercially known way, such as, for example, ethoxylation, to prevent protein deprivation, enhance biocompatibility with, for example, blood and to reduce clotting tendencies.
  • the modules may include a first pump module 5010, as shown in exploded view in Fig. 4 ; a filtration module 5020, as shown in exploded view in Fig. 5 ; an oxygenation module 5030, as shown in exploded view in Fig. 6 ; a debubbler module 5040, as shown in exploded view in Fig. 7 ; and a second pump module 5050, as shown in exploded view in Fig. 8 .
  • the pump modules are each connected to a source of pump fluid and are actuated either manually or by the microprocessor.
  • the support members are preferably similarly shaped.
  • the support members may each be plate-shaped; however, other shapes may also be appropriate.
  • the support members are preferably removably connected by screws or bolts 5065; however, other fasteners for assembling the apparatus may also be appropriate.
  • the first (end) support member 5011 is preferably solid and provides support for the pump module 5010.
  • the first (end) support member 5011 preferably includes a domed-out cavity for receiving pump fluid such as air.
  • Tubing 5011t is provided to allow the pump fluid to enter the pump module 5010.
  • the diaphragm 5013 may be made of any suitable elastic and preferably biocompatible material, and is preferably polyurethane.
  • the third support member 5014 includes a domed-out fluid cavity 5014d and tubing 5014t for receiving fluid, such as, for example, blood or an artificial perfusate, into the cavity 5014d of the pump module 5010.
  • the first pump module, or any of the other modules may also include a port 5014p for sensors or the like.
  • Preferably hemocompatible anti-backflow valves serve to allow unidirectional flow through the pump module 5010.
  • the filtration module 5020 preferably includes a filtration membrane 5021m which forms a boundary of cavity 5014d, a first support member 5022 with a cut-out center area 5022c, a degassing membrane 5022m and second and third support members 5023 and 5024.
  • the filtration membrane 5021m is preferably a 25 ⁇ macro-reticular filtration membrane modified to enhance biocompatibility with, for example, blood and to reduce clotting tendencies (like the other supports, filters and membranes in the device).
  • the degassing membrane 5022m is preferably a 0.2 - 3 ⁇ macro-reticular degassing membrane with a reverse flow aqueous pressure differential of at least 100 mmHg for CO 2 removal surface modified to enhance biocompatibility.
  • the first support 5022 includes tubing 5022t for forwarding fluid into the oxygenation module 30, or another adjacent module, if applicable, after it has passed through the filtration membrane 5021m and along the degassing membrane 5022m.
  • the second support member 5023 of the filtration module 5020 includes a domed-out fluid cavity 5023d and tubing 5023t through which a vacuum may be applied to the cavity 5023d to draw gas out of the fluid through degassing membrane 5022m.
  • the fourth support member 5024 is preferably solid and provides support for the filtration module 5020.
  • the third support member can also include tubing 5024t through which a vacuum may be applied to draw gas out of the fluid through the degassing membrane 5031m of the oxygenation module 5030 as discussed below.
  • the filtration module 5020, or any of the other modules, may also include a port 5023p for sensors or the like.
  • the oxygenation module 5030 includes a degassing membrane 5031m, a first support member 5032, a filtration membrane 5033m, an oxygenation membrane 5034m, a second support member 5034 with a cut-out center area 5034c, and third and fourth support members 5035, 5036.
  • the degassing membrane 5031m is preferably a 0.2 - 3 ⁇ macro-reticular degassing membrane with a reverse flow aqueous pressure differential of at least 100 mmHg surface modified to enhance biocompatibility.
  • the first support member 5032 includes a domed-out fluid cavity 5032d.
  • the surface of the domed-out fluid cavity 5032d preferably forms a tortuous path for the fluid, which enhances the oxygenation and degassing of the fluid.
  • the filtration membrane 5033m is preferably a 25 ⁇ macro-reticular filtration membrane modified to enhance biocompatibility.
  • the oxygenation membrane 5034m is preferably a 0.2 - 1 ⁇ macro-reticular oxygenation membrane with a reverse flow aqueous pressure differential of at least 100 mmHg surface modified to enhance biocompatibility.
  • the debubbler module 5040 includes a first support member 5041, a filtration membrane 5042m, a degassing membrane 5043m, a second support member 5043 having a cut-out center area 5043c, and a third support member 5044.
  • the first support member 5041 has a domed-out fluid cavity 5041d.
  • the filtration membrane 5042m is preferably a 25 ⁇ macro-reticular filtration membrane modified to enhance biocompatibility.
  • the degassing membrane 5043m is preferably a 0.2 - 3 ⁇ macro-reticular degassing membrane with a reverse flow aqueous pressure differential of at least 100 mmHg surface modified to enhance biocompatibility.
  • the second support member 5043 has tubing 5043t for forwarding fluid out of the debubbler module 5040 into the pump module 5050, or another adjacent module, if applicable.
  • the third support member 5044 includes a domed-out cavity 5044d and tubing 5044t through which a vacuum may be applied to draw gas out of the fluid through the degassing membrane 5043m.
  • the second pump module 5050 may correspond to the first pump module 5010. It preferably includes a first support member 5051, a diaphragm 5052, a second support member 5053 with a cut-out center area 5053c, and a third (end) support member 5054.
  • the first support member 5051 includes a domed out fluid cavity 5051d and tubing 5051t for allowing fluid to exit the pump module.
  • the diaphragm 5052 is preferably a polyurethane bladder.
  • the recirculated medical fluid is selectively either directed to the reservoir 15a or 15b not in use along tubing 92a or 92b, respectively, by activating the respective valve LV 2 and LV 5 on the tubing 92a or 92b, or into the organ chamber 40 to supplement the organ bath by activating valve LV 1 .
  • Pressure sensors P3 and P4 monitor the pressure of the medical fluid returned to the bag 15a or 15b not in use.
  • a mechanical safety valve MV 2 is provided on tubing 91 to allow for emergency manual cut off of flow therethrough.
  • tubing 96 and manual valve MV 1 are provided to allow the apparatus to be drained after use and to operate under a single pass mode in which perfusate exiting the organ is directed to waste rather than being recirculated (recirculation mode.)
  • Both the portal side and the hepatic side of perfusion apparatus 2600 preferably have a filter 2630, bubble trap 2640, pressure transducer 2650, temperature transducer 2660, and flow sensor 2670.
  • An additional temperature transducer 2660 may be present in fluid return tubing 2620.
  • the organ may be cooled as discussed above, for example by an ice and water bath 2680 or by a cryogenic fluid. In embodiments using cryogenic fluids, the design should be such that organ freezing is prevented.
  • the modes of operation identified in the table above show options for infusing a liver.
  • the portal valves are set to infuse, which means that portal infusion valve 2695 is open and portal wash valve 2696 is closed.
  • hepatic infusion valve 2685 is closed and hepatic wash valve 2686 is open.
  • the portal pressure is dominant, which means the pressure is controlled by the pressure transducer 2650 on the portal side. In this mode, there is no hepatic infusion.
  • a Portal Priority mode the portal valves and the hepatic valves are set to infuse.
  • the portal pressure is dominant; and therefore, the hepatic side is a slave to the portal side.
  • the portal valves are set to infuse and the hepatic valves switch between an infuse setting and a wash setting.
  • the hepatic side provides the dominant pressure.
  • the portal side provides the dominant pressure.
  • This type of alternating pressure control provides the portal side with a wavy flow and provides the hepatic side with a pulsed flow.
  • Organ diagnostic system 2800 shown in Fig. 28 .
  • Organ diagnostic system 2800 has a computer 2810 and an analyzer 2820. Connected to both computer 2810 and analyzer 2820 is an organ evaluation instrument 2830, also shown in Fig. 29 .
  • Organ diagnostic system 2800 is preferably provided with suitable displays to show the status of the system and the organ.
  • Organ evaluation instrument 2830 has a perfusate chamber 2840 and an organ chamber 2850.
  • Connecting analyzer 2820 and organ evaluation instrument 2830 is a transfer line 2860.
  • Organ diagnostic system 2800 provides analysis of an organ and produces an organ viability index quickly and in a sterile cassette, preferably transferable from perfusion apparatus 1 and/or transporter 1900.
  • the organ viability index is preferably produced by flow and temperature programmed single-pass perfusion and in-line automatic analysis.
  • the analysis may be performed in a multi-pass system, although a beneficial aspect of the single-pass system is that it can be configured with a limited number of sensors and requires only enough perfusate to perform the analysis.
  • Single-pass perfusion also allows for an organ inflow with a perfusate having a known and predetermined chemistry. This increases the flexibility of types and contents of perfusates that may be delivered, which can be tailored and modified to the particular analysis in process.
  • Fig. 29 shows a perspective view of organ evaluation instrument 2830.
  • Organ evaluation instrument 2830 has a perfusate chamber 2840 and an organ chamber 2850.
  • Organ chamber 2850 may be insulated and preferably has a lid 2910 that may be removable or may be hinged.
  • Organ chamber 2850 is preferably configured to receive cassette 65, preferably without opening cassette 65 or jeopardizing the sterility of the interior of cassette 65.
  • Cassette 65 and organ chamber 2850 are preferably constructed to fit or mate such that efficient heat transfer is enabled.
  • the geometric elements of cassette 65 and organ chamber 2850 are preferably constructed such that when cassette 65 is placed within organ chamber 2850, the elements are secure for analysis.
  • a port 2920 is also provided to connect transfer line 2860.
  • Fig. 30 shows a single-pass fluid system of organ diagnostic system 2800.
  • the initial perfusion fluids 3000 are contained in a chamber 3010.
  • Chamber 3010 is preferably temperature controlled by a heating and cooling system. Fluid flow within the system is monitored by flow sensor 3020 and controlled by signaling to pinch valves 3030 and pumps 3040.
  • the fluid system also provides a bubble trap 3050, a pressure transducer 3060 and a temperature transducer 3070.
  • Heat exchanger 3080 provides temperature control and heating and cooling to the fluid within the system prior to organ perfusion.
  • the organ is perfused in cassette 65.
  • the fluid in the organ bath may be collected, or the venous outflow may be captured, to be analyzed.
  • the fluid is collected and passed via transfer line 2860 to analyzer 2820. Transfer line 2860 may also be provided with a separate heating and cooling unit. After the fluid is analyzed, it may be collected in a waste receptacle 3090.
  • Fig. 31 shows a logic circuit for organ diagnostic system 2800.
  • the computer provides control parameters and receives results and data from the analyzer.
  • the logic circuit shows inputs from the sensors to the microcontroller and outputs to hardware elements, such as perfusate coolers, perfusate heaters, pinch valves, pumps, transferline heater/cooler and displays.
  • the method according to the invention preferably utilizes apparatus such as that discussed above to perfuse an organ to sustain, monitor and/or restore the viability of an organ and/or to transport and/or store the organ.
  • Preservation of the viability of an organ is a key factor to a successful organ transplant.
  • Organs for transplant are often deprived of oxygen (known as ischemia) for extended periods of time due to disease or injury to the donor body, during removal of the organ from the donor body and/or during storage and/or transport to a donee body.
  • the perfusion, diagnostic, and/or transporter apparatus of the present invention have the ability to detect the cell chemistry of an organ to be transplanted in order to adjust the perfusate and control the cellular metabolism to repair ischemic damage to the organ and to prevent reperfusion injury.
  • One specific outcome of ischemic injury may be apoptosis or programmed cell death.
  • Specific agents and additives provided to an organ by the perfusion, diagnostic and/or transporter apparatus, under conditions controlled by the particular apparatus, may interrupt, decrease and/or reverse apoptosis.
  • an organ or tissue is treated ex vivo by mechanical, physical, chemical or genetic manipulation and/or modification to treat disease and/or treat damage to and/or enhance the properties of the organ or tissue.
  • An organ or tissue sample may be removed from a first body, modified, treated and/or analyzed outside the first body and either returned to the first body or transplanted to a second body.
  • An advantage of the apparatus is that it enlarges the time that an organ may be available for ex vivo treatment, e.g., for hours (e.g. 2, 4, 6, 8, 10, 12 or more hours) or even days (e.g. 2, 4, 6, 8, 10, 12 or more days) or weeks (e.g. 1, 2, 3, 4, 5, 6, 7, 8 or more weeks).
  • the perfusion, diagnostic and/or transporter apparatus of the present invention may be used to provide particular solutions or chemicals to an organ or tissue or may be used to perform particular treatments including flushing or washing an organ or tissue with particular solutions or chemicals.
  • Ex vivo treatments may be performed on tissue or an organ to be transplanted or may be performed on tissue or an organ that has been removed from a patient and is to be returned to the patient after the desired procedure is performed.
  • Ex vivo treatments include but are not limited to treatment of tissue or an organ that has endured a period or periods of ischemia and/or apoxia.
  • Ex vivo treatments may involve performing surgical techniques on an organ, such as cutting and suturing an organ, for example to remove necrotic tissue.
  • Any surgical or other treatment technique that may be performed on tissue or an organ in vivo may also be performed on tissue or an organ ex vivo.
  • the benefit of such ex vivo treatment may be seen, for example, in the application of radiation or chemotherapy to treat a tumor present in or on an organ, to prevent other portions of the patient from being subjected to extraneous radiation or chemotherapy during treatment.
  • the perfusion and transporter apparatus of the present invention also provide additional time for a physician to maintain the tissue or organ before, during and/or after performing a particular technique on the tissue or organ.
  • the perfusion, diagnostic and/or transporter apparatus of the present invention may deliver substances such as chemical compounds, natural or modified antibodies, immunotoxins or the like, to an organ and may assist the organ to adsorb, absorb or metabolize such substances to increase the likelihood that the organ will not be rejected. These substances may also mask the organ by blocking, killing, depleting and/or preventing the maturation of allostimulatory cells (dendritic cells, passenger leukocytes, antigen presenting cells, etc.) so that the recipient's immune system does not recognize it or otherwise recognizes the organ as autologous. An organ may be treated just prior to transplantation or may be pretreated hours, days or weeks before transplantation. Such techniques are further described in U.S. Provisional Patent Application No. , filed August 25, 2000, Attorney Docket No. 100034, the entire disclosure of which is hereby incorporated by reference.
  • an organ may be tested for the effects of various treatments and/or substances on the organ or tissue ex vivo.
  • the perfusion, diagnostic and/or transporter apparatus may be used to perfuse blood or a synthetic blood substitute through an organ while monitoring the organ and the organ outflow to analyze the condition of the organ and/or to determine the effect on it of the various treatments.
  • Preferred methods according to the present invention focus on three concepts in order to preserve an organ's viability prior to transplant of the organ into a donee body -- treating the cellular mitochondria to maintain and/or restore pre-ischemia energy and enzyme levels, preventing general tissue damage to the organ, and preventing the washing away of or damage to the vascular endothelial lining of the organ.
  • the mitochondria are the energy source in cells. They need large amounts of oxygen to function. When deprived of oxygen, their capacity to produce energy is reduced or inhibited. Additionally, at temperatures below 20 °C the mitochondria are unable to utilize oxygen to produce energy.
  • the mitochondria are provided with sufficient amounts of oxygen so that pre-ischemia levels of reserve high energy nucleotide, that is, ATP levels, in the organ reduced by the lack of oxygen are maintained and/or restored along with levels of enzymes that protect the organ's cells from free radical scavengers. Pyruvate rich solutions, such as that disclosed in U.S. Patent No.
  • the normothermic perfusion fluid may contain pyruvate but may also contain little or no pyruvate. For example, it can contain less than 6 mM of pyruvate, 5 mM, 4 mM, or even no pyruvate.
  • Other known preservation solutions such as that disclosed in U.S. Patent No. 5,599,659 , also fail to contain sufficient oxygen to restore and/or maintain pre-ischemia energy and enzyme levels.
  • the organ After maintaining and/or restoring the organ's pre-ischemia energy levels by perfusing the organ with an oxygen rich first medical fluid at normothermic or near-normothermic temperatures (the normothermic mode), the organ is perfused with a second medical fluid at hypothermic temperatures (the hypothermic mode).
  • the hypothermic temperatures slow the organ's metabolism and conserve energy during storage and/or transport of the organ prior to introduction of the organ into a donee body.
  • the medical fluid utilized in the hypothermic mode contains little or no oxygen, which cannot be utilized by mitochondria to produce energy below approximately 20°C.
  • the medical fluid may include antioxidants and other tissue protecting agents, such as, for example, ascorbic acid, glutathione, water soluble vitamin E, catalase, or superoxide dismutase to protect against high free radical formation which occurs at low temperatures due to the reduction in catalase/superoxide dismutase production.
  • tissue protecting agents such as, for example, ascorbic acid, glutathione, water soluble vitamin E, catalase, or superoxide dismutase to protect against high free radical formation which occurs at low temperatures due to the reduction in catalase/superoxide dismutase production.
  • various drugs and agents such as hormones, vitamins, nutrients, antibiotics and others may be added to either solution where appropriate.
  • vasodilators such as, for example, peptides, may be added to the medical fluid to maintain flow even in condition of injury.
  • the organ Prior to any normothermic perfusion with the oxygen rich first medical fluid at normothermic temperatures, the organ may be flushed with a medical solution containing little or no oxygen and preferably containing antioxidants.
  • the flushing is usually performed at hypothermic temperatures but can, if desired and/or as necessary, be performed at normothermic or near-normothermic temperatures. Flushing can be followed by one or more of hypothermic perfusion, normothermic perfusion, and/or static storage, in any necessary and/or desired order. In some cases, normothermic perfusion may not be necessary.
  • the normothermic perfusion with or without prior hypothermic flushing, may also be performed on an organ that has already been subjected to hypothermic temperatures under static or perfusion conditions, as well as on normothermic organs.
  • the organ may optionally again be perfused at normothermic temperatures in vivo, or allowed to warm up from the circulation of the donee.
  • the organ can be harvested from the donor under beating heart conditions. Following harvesting, the organ can be flushed, such as with any suitable solution or material including, but not limited to VIASPAN (a preservation solution available from DuPont), other crystalloid solution, dextran, HES (hydroxyethyl starch), solutions described in U.S. Patent Application 09/628,311, filed July 28, 2000 , the entire disclosure of which is hereby incorporated by reference, or the like.
  • the organ can then be stored statically, for example, at ice temperatures (for example of from about 1 to about 10°C).
  • the organ can again be harvested under beating heart conditions, followed by flushing, preferably at hypothermic temperatures.
  • the organ can be stored in a suitable transporter at, for example, ice temperatures.
  • Flow to the organ can be controlled by a set pressure maximum, where preset pressure minimum and pressure maximum values control the pulse wave configuration.
  • the organ can be placed in the MOR.
  • a suitable perfusate can be used, such as a crystalloid solution, dextran or the like, and preferably at hypothermic temperatures.
  • an organ having minimal WIT and minimal vascular occlusion can be harvested under non-beating heart conditions.
  • the organ can flushed, preferably at hypothermic temperatures and, if necessary, stored for transport in a suitable transporter at, for example, ice temperatures.
  • flow to the organ can be controlled by a set pressure maximum, where preset pressure minimum and pressure maximum values control the pulse wave configuration.
  • the organ can be placed in the MOR, either for extended storage and/or for damage assessment.
  • a suitable perfusate can be used, such as a crystalloid solution, dextran or the like, and preferably at hypothermic temperatures.
  • the hypothermic temperatures are from about 4 to about 10°C, but higher or lower temperatures can be used, as desired and/or necessary.
  • the perfusate solution contains specific markers to allow for damage assessment, although damage assessment can also be made by other known procedures.
  • a second perfusion can be utilized, preferably at normothermic temperatures. Any suitable perfusion solution can be used for this process, including solutions that contain, as desired, oxygenated media, nutrients, and/or growth factors.
  • the normothermic temperatures are from about 12 to about 24°C, but higher or lower temperatures can be used, as desired and/or necessary.
  • the normothermic perfusion can be conducted for any suitable period of time, for example, for from about 1 hour to about 24 hours.
  • a suitable perfusate can be used, such as a crystalloid solution, dextran or the like, and preferably at hypothermic temperatures.
  • the hypothermic temperatures are from about 4 to about 10°C, but higher or lower temperatures can be used, as desired and/or necessary.
  • the perfusate solution contains specific markers to allow for damage assessment, although damage assessment can also be made by other known procedures.
  • a second perfusion can be utilized, preferably at normothermic temperatures. Any suitable perfusion solution can be used for this process, including solutions that contain, as desired, oxygenated media, nutrients, and/or growth factors.
  • the normothermic temperatures are from about 12 to about 24°C, but higher or lower temperatures can be used, as desired and/or necessary.
  • the normothermic perfusion can be conducted for any suitable period of time, for example, for from about 1 hour to about 24 hours. If desired, and particularly in the event that vascular occlusion is determined or assumed to be present, a further perfusion can be conducted at higher normothermic temperatures, for example of from about 24 to about 37°C. This further perfusion can be conducted using a suitable solution that contains a desired material to retard the vascular occlusion.
  • Such materials include, for example, clotbusters such as streptokinase.
  • the organ is preferably returned to a hypothermic profusion using, for example, a suitable solution such as a crystalloid solution, dextran or the like, and preferably at hypothermic temperatures.
  • a suitable solution such as a crystalloid solution, dextran or the like
  • the organ can then be returned to the transporter for transport to the implant site.
  • the organ cassette according to the present invention allows an organ(s) to be easily transported to an organ recipient and/or between organ perfusion, diagnostic and/or portable transporter apparatus, such as, for example, transporter 1900 described above or a conventional cooler or a portable container such as that disclosed in co-pending U.S. Application No. 09/161,919 .
  • transporter 1900 and/or cassette 65 may include a Global Positioning System (GPS) (not shown) to allow tracking of the location of the organ(s).
  • GPS Global Positioning System
  • the apparatus may also include a data logger and/or transmitter (not shown) to allow monitoring of the organ(s) at the location of the apparatus or at another location.
  • the apparatus discussed above can operate in two modes: a normothermic perfusion mode and a hypothermic perfusion mode.
  • the normothermic perfusion mode will be discussed first followed by a discussion of hypothermic perfusion mode. Repetitive description will be omitted as much as possible.
  • an organ is perfused for preferably 1 ⁇ 2 to 6 hours, more preferably 1 ⁇ 2 to 4 hours, most preferably 1 ⁇ 2 to 1 hour, with a medical fluid maintained preferably within a range of approximately 10°C to 38°C, more preferably 12°C to 35°C, most preferably 12°C to 24°C or 18°C to 24°C (for example, room temperature 22-23°C) by the thermoelectric unit 30a disposed in heat exchange communication with the medical fluid reservoir 10.
  • the medical fluid is preferably an oxygenated cross-linked hemoglobin-based bicarbonate solution.
  • Cross-linked hemoglobin-based medical fluids can deliver up to 150 times more oxygen to an organ per perfusate volume than, for example, a simple University of Wisconsin (UW) gluconate type perfusate. This allows normothermic perfusion for one to two hours to partially or totally restore depleted ATP levels.
  • UW University of Wisconsin
  • the invention is not limited to this preservation solution.
  • Other preservation solutions such as those disclosed in U.S. Patents Nos. 5,149,321 , 5,234,405 and 5,395,314 and co-pending U.S. Patent Applications Nos. 08/484,601 and U.S. Patent Application 09/628,311, filed July 28, 2000 , Attorney Docket No. 101311, the entire disclosures of which are hereby incorporated by reference, may also be appropriate.
  • the medical fluid is fed directly to an organ disposed within the organ chamber 40 from one or the other of bags 15a, 15b via tubing 50a,50b,50c or 50d,50e,50c, respectively.
  • the organ is perfused at flow rates preferably within a range of approximately 3 to 5 ml/gram/min.
  • Pressure sensor P1 relays the perfusion pressure to the microprocessor 150, which varies the pressure supplied by the pressure source 20 to control the perfusion pressure and/or displays the pressure on the control and display areas 5a for manual adjustment.
  • the pressure is preferably controlled within a range of approximately 10 to 100 mm Hg, preferably 50 to 90 mm Hg, by the combination of the pressure source 20 and pressure cuff 15a, 15b in use and the stepping motor/cam valve 65.
  • the compressor and cuffs provide gross pressure control.
  • the stepping motor/cam valve 65 (or other variable valve or pressure regulator), which is also controlled by the operator, or by the microprocessor 150 in response to signals from the pressure sensor P1, further reduces and fine tunes the pressure and/or puts a pulse wave on the flow into the organ 60. If the perfusion pressure exceeds a predetermined limit, the stepping motor/cam valve 65 may be activated to shut off fluid flow to the organ 60.
  • heart and kidneys are preferably perfused at a pressure of approximately 10 to 100 mm Hg and a flow rate of approximately 3 to 5 ml/gram/min. for up to approximately 2 to 4 hours at normothermic temperatures to maintain and/or restore the viability of the organ by restoring and/or maintaining pre-ischemia energy levels of the organ, and are then preferably perfused at a pressure of approximately 10 to 30 mm Hg and a flow rate of approximately 1 to 2 ml/gram/min. for as long as approximately 72 hours to 7 days at hypothermic temperatures for storage and/or transport.
  • these criteria will vary depending on the condition of the particular organ, the donor body and/or the donee body and/or on the size of the particular organ.
  • One of ordinary skill in the art can select appropriate conditions without undue experimentation in view of the guidance set forth herein.
  • Effluent medical fluid collects in the bottom of the organ chamber 40 and is maintained within the stated temperature range by the second thermoelectric unit 30b.
  • the temperature sensor T2 relays the organ temperature to the microprocessor 150, which controls the thermoelectric unit 30a to adjust the temperature of the medical fluid and organ bath to maintain the organ 60 at the desired temperature, and/or displays the temperature on the control and display areas 5c for manual adjustment.
  • Collected effluent medical fluid is pumped out by the pump 80 via tubing 81 through the filter unit 82 and then returned to the organ bath. This filters out surgical and/or cellular debris from the effluent medical fluid and then returns filtered medical fluid to act as the bath for the organ 60.
  • the level sensor L2 senses that a predetermined level of effluent medical fluid is present in the organ chamber 40 (preferably enough to maintain the organ 60 immersed in effluent medical fluid)
  • additional effluent medical fluid is pumped out by the pump 90 through tubing 91.
  • the temperature sensor T1 relays the temperature of the organ bath to the microprocessor 150, which controls the thermoelectric unit 30b to adjust the temperature of the medical fluid to maintain the organ 60 at the desired temperature and/or displays the temperature on the control and display area 5c for manual adjustment and monitoring.
  • the medical fluid can be directed to waste in a single pass mode or recirculated eventually back to the organ and/or bath (recirculation mode.)
  • the recirculated medical fluid is pumped through the CO 2 scrubber/O 2 membrane 100.
  • the medical fluid passes over the hydrophobic macroporous membrane with a hydrophilic coating (for example, Hypol) and a low vacuum is applied on the opposite side by activating valve VV 1 which removes CO 2 from the recirculated medical fluid.
  • a hydrophilic coating for example, Hypol
  • a portion of the medical fluid then enters the oxygenator 110 (for example, a JOSTRATM oxygenator) and a portion is diverted therearound passing via tubing 111 though the pH, pO 2 , pCO 2 , LDH, T/GST and Tprotein sensor V1.
  • the oxygenator 110 for example, a JOSTRATM oxygenator
  • two gases preferably 100% oxygen and 95/5% oxygen/carbon dioxide, are respectively placed on the opposite sides of the membrane depending on the pH level of the diverted medical fluid.
  • the gases are applied at a pressure of up to 200 mm Hg, preferably 50 to 100 mm Hg, preferably through a micrometer gas valve GV 3 .
  • the cross-linked hemoglobin-based bicarbonate medical fluid may be formulated to require a pCO 2 of approximately 40 mm Hg to be at the mid point (7.35) of a preferred pH range of 7.25-7.45.
  • an organ is perfused with a cooled medical fluid, preferably at a temperature within a range of approximately 1°C to 15°C, more preferably 4 °C to 10 °C, most preferably around 10 °C.
  • the medical fluid is preferably a crystalloid perfusate without oxygenation and preferably supplemented with antioxidants and other tissue protecting agents, such as, for example, ascorbic acid, glutathione, water soluble vitamin E, catalase, or superoxide dismutase.
  • the medical fluid may be provided to the organ 60 intermittently (e.g., every two hours at a flow rate of up to approximately 100 ml/min.), or at a slow continuous flow rate (e.g., up to approximately 100 ml/min.) over a long period of time. Intermittent perfusion can be implemented in the single pass mode or recirculation mode.
  • the pump 80, filter unit 82 and tube 81 may be used to filter the organ bath along with use of the pH, pO 2 , pCO 2 , LDH, T/GST and Tprotein sensor; however, because the organ is unable to utilize oxygen at hypothermic temperatures, the oxygenator is not used. If desired and/or necessary, adequate oxygen can be obtained from filtered room air or other suitable source.
  • Both the perfusate flow and the temperature regulation can be automatically controlled. Such automatic control allows a rapid and reliable response to perfusion conditions during operation.
  • Automatic flow control can be based on the parameters measured from the system, including the perfusate flow rate, the perfusate pH exiting the organ, the organ inlet pressure or timed sequences such as pre-selected flow rates or switching between perfusate modes.
  • the flow control is based on pressure monitoring of the perfusate inflow into the organ.
  • the benefits of automatic flow control include maintaining proper oxygenation and pH control while operating under continuous flow or controlled intermittent flow.
  • Thermal control of the thermoelectric devices (TED) can regulate the temperature of the organ cassette or container and the perfusate reservoir. The thermal control is based on thermal measurements made for example by thermistor probes in the perfusate solution or inside the organ or by sensors in the TED.
  • the automatic control is preferably effected by an interactive control program using easily operated menu icons and displays.
  • the parameters may be prestored for selection by a user or programmed by the user during operation of the system.
  • the control program is preferably implemented on a programmed general purpose computer.
  • the controller can also be implemented on a special purpose computer, a programmed microprocessor or microcontroller and peripheral integrated circuit elements, an ASIC or other integrated circuit, a digital signal processor, a hardwired electronic or logic circuit such as a discrete element circuit, a programmable logic device such as a PLD, PLA, FPGA or PAL, or the like.
  • any device capable of implementing a finite state machine that is in turn capable of implementing the control process described herein may be used.
  • the control program is preferably implemented using a ROM. However, it may also be implemented using a PROM, an EPROM, an EEPROM, an optical ROM disk, such as a CD-ROM or DVD-ROM, and disk drive or the like. However, if desired, the control program may be employed using static or dynamic RAM. It may also be implemented using a floppy disk and disk drive, a writable optical disk and disk drive, a hard drive, flash memory or the like.
  • the basic steps of operation to control perfusion of one or more organs include first inputting organ data.
  • the organ data includes at least the type of organ and the mass.
  • the program will prompt the user to select one or more types of perfusion modes.
  • the types of perfusion modes include hypothermic perfusion, normothermic perfusion, and sequential perfusion using both normothermic and hypothermic perfusion.
  • hypothermic perfusion includes hypothermic perfusion, normothermic perfusion, and sequential perfusion using both normothermic and hypothermic perfusion.
  • the user can select between medical fluids at different temperatures.
  • the system includes default values based on previously stored values appropriate for the particular organ.
  • the user may also select intermittent perfusion, single pass perfusion, and recirculation perfusion. Depending on the type of perfusion selected, aerobic or anaerobic medical fluids may be specified.
  • the flow control selector selects flow control based on at least one of perfusate flow rate, perfusate pH, organ inlet pressure and timed sequences. In the preferred embodiment, the flow control is based on detected pressure at the perfusion inlet to the organ. The flow of the medical fluid is then based on the selected perfusion mode and flow control.
  • the conditions experienced by the system, in particular by the organ and the perfusate are detected and monitored.
  • the detected operating conditions are compared with prestored operating conditions.
  • a signal can then be generated indicative of organ viability based on the comparison.
  • the various detectors, sensors and monitoring devices are described above, but include at least a pressure sensor, a pH detector, an oxygen sensor and a flow meter.
  • the control system may also include a thermal controller for controlling temperature of at least one of the perfusate and the organ.
  • the thermal controller can control the temperature of the medical fluid reservoirs and the organ container by controlling the TEDs.
  • temperature sensors are connected to the controller to facilitate monitoring and control.
EP10182445.6A 2000-08-25 2001-08-27 Appareil pour tenir d'organes Expired - Lifetime EP2308292B1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US09/645,525 US6673594B1 (en) 1998-09-29 2000-08-25 Apparatus and method for maintaining and/or restoring viability of organs
EP01966245A EP1317175B1 (fr) 2000-08-25 2001-08-27 Appareil de conservation et/ou restauration de la viabilite d'organes
PCT/US2001/026591 WO2002026034A2 (fr) 2000-08-25 2001-08-27 Appareil et procede de conservation et/ou restauration de la viabilite d'organes

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EP01966245.1 Division 2001-08-27

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EP2308292A2 true EP2308292A2 (fr) 2011-04-13
EP2308292A3 EP2308292A3 (fr) 2011-08-03
EP2308292B1 EP2308292B1 (fr) 2020-08-05

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EP10182337.5A Expired - Lifetime EP2308291B1 (fr) 2000-08-25 2001-08-27 Procédé pour tenir d'un organe
EP10179512.8A Expired - Lifetime EP2258175B1 (fr) 2000-08-25 2001-08-27 Appareil de conservation et/ou restauration de la viabilite d'organes
EP10182445.6A Expired - Lifetime EP2308292B1 (fr) 2000-08-25 2001-08-27 Appareil pour tenir d'organes
EP10180682.6A Expired - Lifetime EP2301340B1 (fr) 2000-08-25 2001-08-27 Appareil portatif pour transporter d'organes
EP10179481A Withdrawn EP2301334A3 (fr) 2000-08-25 2001-08-27 Procédé pour transporter et stocker d'organes
EP10181340.0A Expired - Lifetime EP2301341B1 (fr) 2000-08-25 2001-08-27 Appareil pour la perfusion d'un foie
EP10179870.0A Expired - Lifetime EP2301337B1 (fr) 2000-08-25 2001-08-27 Kit pour le support d'un organe
EP10181356.6A Expired - Lifetime EP2301342B1 (fr) 2000-08-25 2001-08-27 Procédé pour controller l'opération d'un transporteur
EP10183797A Withdrawn EP2308293A3 (fr) 2000-08-25 2001-08-27 Procédé pour maintenir et/ou restaurer la viabilité d'organes
EP01966245A Expired - Lifetime EP1317175B1 (fr) 2000-08-25 2001-08-27 Appareil de conservation et/ou restauration de la viabilite d'organes
EP10179853.6A Expired - Lifetime EP2301336B1 (fr) 2000-08-25 2001-08-27 Procédé de commande de la perfusion d'un organe ex vivo et système de commande correspondant
EP10179494.9A Expired - Lifetime EP2301335B1 (fr) 2000-08-25 2001-08-27 Dispositif de transport d'organe
EP10183836.5A Expired - Lifetime EP2308294B1 (fr) 2000-08-25 2001-08-27 Procédé pour déterminer des paramètres de perfusion et former un enregistrement de la transplantation
EP10180598.4A Expired - Lifetime EP2301339B1 (fr) 2000-08-25 2001-08-27 Procédé pour maintenir et/ou restaurer la viabilité d'organes
EP10179523.5A Expired - Lifetime EP2258176B1 (fr) 2000-08-25 2001-08-27 Procede de conservation et/ou restauration de la viabilite d'organes
EP10179878A Withdrawn EP2301338A3 (fr) 2000-08-25 2001-08-27 Appareil pour perfuser d'organes

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EP10180682.6A Expired - Lifetime EP2301340B1 (fr) 2000-08-25 2001-08-27 Appareil portatif pour transporter d'organes
EP10179481A Withdrawn EP2301334A3 (fr) 2000-08-25 2001-08-27 Procédé pour transporter et stocker d'organes
EP10181340.0A Expired - Lifetime EP2301341B1 (fr) 2000-08-25 2001-08-27 Appareil pour la perfusion d'un foie
EP10179870.0A Expired - Lifetime EP2301337B1 (fr) 2000-08-25 2001-08-27 Kit pour le support d'un organe
EP10181356.6A Expired - Lifetime EP2301342B1 (fr) 2000-08-25 2001-08-27 Procédé pour controller l'opération d'un transporteur
EP10183797A Withdrawn EP2308293A3 (fr) 2000-08-25 2001-08-27 Procédé pour maintenir et/ou restaurer la viabilité d'organes
EP01966245A Expired - Lifetime EP1317175B1 (fr) 2000-08-25 2001-08-27 Appareil de conservation et/ou restauration de la viabilite d'organes
EP10179853.6A Expired - Lifetime EP2301336B1 (fr) 2000-08-25 2001-08-27 Procédé de commande de la perfusion d'un organe ex vivo et système de commande correspondant
EP10179494.9A Expired - Lifetime EP2301335B1 (fr) 2000-08-25 2001-08-27 Dispositif de transport d'organe
EP10183836.5A Expired - Lifetime EP2308294B1 (fr) 2000-08-25 2001-08-27 Procédé pour déterminer des paramètres de perfusion et former un enregistrement de la transplantation
EP10180598.4A Expired - Lifetime EP2301339B1 (fr) 2000-08-25 2001-08-27 Procédé pour maintenir et/ou restaurer la viabilité d'organes
EP10179523.5A Expired - Lifetime EP2258176B1 (fr) 2000-08-25 2001-08-27 Procede de conservation et/ou restauration de la viabilite d'organes
EP10179878A Withdrawn EP2301338A3 (fr) 2000-08-25 2001-08-27 Appareil pour perfuser d'organes

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US (2) US6673594B1 (fr)
EP (16) EP2308291B1 (fr)
JP (5) JP4958380B2 (fr)
AU (1) AU2001286777A1 (fr)
CA (1) CA2420848A1 (fr)
WO (1) WO2002026034A2 (fr)

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EP2308293A2 (fr) 2011-04-13
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EP2301334A3 (fr) 2011-07-27
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EP2308292A3 (fr) 2011-08-03
EP2308291A3 (fr) 2011-07-20
JP2012092113A (ja) 2012-05-17
EP1317175B1 (fr) 2012-08-08
EP2301342A2 (fr) 2011-03-30
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JP2012092112A (ja) 2012-05-17
JP2004513889A (ja) 2004-05-13
EP1317175A2 (fr) 2003-06-11
EP2301337A2 (fr) 2011-03-30
US20110183310A1 (en) 2011-07-28
JP5544349B2 (ja) 2014-07-09
EP2308292B1 (fr) 2020-08-05
EP2258176A3 (fr) 2011-07-27
EP2301342B1 (fr) 2018-08-15
EP2301336A3 (fr) 2012-04-25
EP2301336B1 (fr) 2018-08-08
EP2301335A3 (fr) 2011-08-31
EP2308294A2 (fr) 2011-04-13
EP2258176B1 (fr) 2020-03-25
EP2258175A3 (fr) 2011-12-14
EP2301337B1 (fr) 2020-10-07
EP2301335B1 (fr) 2017-12-27
WO2002026034A2 (fr) 2002-04-04
EP2301338A3 (fr) 2012-01-04
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US8323954B2 (en) 2012-12-04
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US6673594B1 (en) 2004-01-06
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